The long-range goal of this proposal is to determine if pegylated Interferon-a-2A (Peg-IFN-a2A) can sustain HIV-1 suppression in the absence of Anti-Retroviral Therapy (ART) in infected individuals. The short-range goal of this study is to compare two different doses of Roche Pegasys(r) Peg-IFN-a2A, 90 and 180 [unreadable]g per week, for their ability to maintain viral control when initiated at the time of ART interruption in HIV-infected suppressed patients (VL<50 copies /ml) for 24 weeks or more, as determined by observing >0.5 log difference in viral set-points (delta viral load) obtained at two sequential 12 weeks ART discontinuations, with Peg-IFN-a2A administered only during the second discontinuation. Primary analysis will be an "intent to treat" analysis and will address the hypothesis that two different doses of Peg-IFN a2A (90 and 180 [unreadable]g/week) will be similarly effective at inhibiting viral replication as defined by <0.5 log difference between the delta viral loads of each experimental arm. Secondary aims will evaluate: (1) safety, tolerability and dose-dependent, treatment-associated toxicity, of 50 weekly administrations of Peg-IFN a2A at 180 [unreadable]g or 90 [unreadable]g/week (in association with ART for the initial 2 weeks, followed by 48 weeks of Peg-IFN-a2A, alone); (2) the potential for Peg-IFNa2A-mediated (direct and immune-mediated) antiviral activity to extend viral control over a period of 48 weeks after ART interruption; (3) innate immunity outcomes correlated to Peg-IFNa2A dose and antiviral activity, by monitoring NK and DC subset changes and the ability to maintain/enhance innate immune functions (DC secretory responses, NK antiviral cytotoxic responses); (4) adaptive immunity outcomes correlated to Peg-IFNa2A dose and antiviral activity by monitoring T-cell subsets changes and the ability to maintain cell-mediated proliferative and cytokine responses against recall antigens (HIV-1 gag p55). Completion of this proposal will address the need to develop safe and tolerable alternative therapy strategies for chronic HIV infection, and help determine the anti-retroviral role of ART-reconstituted innate arid adaptive immunity effectors activated by systemic Peg-IFNa2A therapy. This multi-site randomized, open-label clinical study represents a multidisciplinary research effort by the Wistar Institute, The Jonathan Lax Center for the Treatment of Immune Disorders (Philadelphia FIGHT), The Infectious Disease Division for the University of Pennsylvania, The AIDS clinic of Drexel University Medical College, the University of Massachusetts' Department of Biostatistics, BD Biosciences, Roche, Inc. and The Gladstone Institute of Virology and Immunology. [unreadable] [unreadable]